CN113797157A - Breviscapine injectable hydrogel and preparation method and application thereof - Google Patents
Breviscapine injectable hydrogel and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a breviscapine injectable hydrogel and a preparation method and application thereof. The preparation method of the breviscapine injectable hydrogel comprises the following steps: dissolving breviscapine in alkaline aqueous solution, adding metal ion solution, and performing ultrasonic treatment to obtain breviscapine injectable hydrogel. The breviscapine injectable hydrogel does not need chemical modification and other drug carriers, and has high drug utilization rate, good biocompatibility and high safety; the hydrogel has shear thinning and injectability, and can be used for injection administration; the hydrogel preparation method is green and simple.
Description
Technical Field
The invention relates to the technical field of medicinal preparations, in particular to a breviscapine injectable hydrogel and a preparation method and application thereof.
Background
Breviscapine (breviscapine) is a flavonoid compound extracted from herba Erigerontis as Chinese herbal medicine for promoting blood circulation and removing blood stasis. The breviscapine is a mixture of scutellarin (scutellarin) and breviscapine, wherein the scutellarin accounts for 80% of the total weight of the breviscapine and is the main component of the breviscapine. Scutellarin is also called scutellarin (scutellarin), the chemical name of which is 4-hydroxy baicalein-7-O-glucuronide, and the structural formula of the scutellarin is shown as follows:
breviscapine has antithrombotic, blood flow increasing, blood vessel dilating, microcirculation improving, and blood plasma fibrin content reducing effects. Breviscapine is widely used for treating coronary heart disease, angina pectoris, cerebral infarction and cerebral ischemia-reperfusion injury. However, breviscapine has the disadvantages of poor water solubility, poor chemical stability, short biological half-life, low blood brain barrier transmittance and the like.
At present, the clinical forms of breviscapine mainly comprise breviscapine freeze-dried powder, breviscapine injection and breviscapine tablets. Breviscapine is a weakly acidic drug, and has extremely low bioavailability due to dissociation in intestinal tract. The common breviscapine granules and the common breviscapine tablets have low bioavailability and short effective blood concentration maintaining time, and multiple times of administration are needed clinically, which not only causes the fluctuation of the blood concentration in a peak valley, but also brings troubles to patients. The liquid preparation has poor storage stability and low safety, and the pharmacological activity of the liquid preparation needs to be further improved, which causes certain limitation on the industrialization and clinical application of the liquid preparation. Therefore, there is a need to develop a new formulation of breviscapine, which can release breviscapine drug safely and in a long-term manner, and improve the utilization rate and therapeutic effect of the drug.
Disclosure of Invention
The invention mainly aims to provide a breviscapine injectable hydrogel and a preparation method and application thereof, and aims to solve the problems of low bioavailability, short effective blood concentration maintenance time and low safety of the conventional breviscapine medicament dosage form.
In order to achieve the above object, according to one aspect of the present invention, there is provided a breviscapine injectable hydrogel, the microstructure of which is a three-dimensional network structure, the breviscapine injectable hydrogel being formed by self-assembly of breviscapine in an alkaline aqueous solution in coordination with metal ions.
The invention utilizes carboxyl in the small molecular drug breviscapine to form carboxylate ions in an alkaline solution, and then the carboxylate ions and metal ions are self-assembled to form the injectable hydrogel through non-covalent acting forces such as hydrogen bonds, pi-pi accumulation, hydrophobic action, coordination action and the like. In the system, a dynamic and reversible coordination bond is formed between a breviscapine drug molecule and a metal ion, the hydrogel can be quickly sheared and thinned under certain stress, and the original gel state can be quickly recovered after injection.
The breviscapine injectable hydrogel can be directly injected and slowly releases breviscapine drug molecules. The hydrogel is formed by self-assembly of drug molecules, a carrier is not required to be added, toxic and side effects caused by the adoption of liposome, polymer microspheres, micelles, nanoparticles, macromolecules and the like as drug carriers in the prior art are avoided, and the drug loading capacity is improved. The breviscapine injectable hydrogel solves the problems of poor solubility, easy and rapid removal and the like of breviscapine, and has very important clinical significance.
Furthermore, the content of the breviscapine in the breviscapine injectable hydrogel is 0.8 wt% -4.0 wt%. Through experimental research, when the content of the breviscapine is lower than the minimum gelling concentration of 0.8 wt%, hydrogel cannot be formed; when the content of breviscapine is higher than the maximum concentration of 4.0 wt%, it may cause the hydrogel to be non-uniformly transparent. Therefore, the content of breviscapine in the hydrogel is preferably in the range of 0.8 wt% to 4.0 wt%.
Further, the pH of the alkaline aqueous solution is 10 to 12.8, and the pH of the hydrogel is 7.0 to 7.4.
Further, the alkaline aqueous solution is a PBS buffer solution, a sodium hydroxide solution or a potassium hydroxide solution.
Further, the molar ratio of breviscapine to metal ions is 1: (0.33-1.2). Researches show that the molar ratio of the breviscapine to the metal ions is better than that of the obtained hydrogel in the range; if too many metal ions are used, the hydrogel is not uniform, is not transparent and can cause cytotoxicity; too little metal ion can result in failure to self-assemble to form a hydrogel.
Further, the metal ion is Zn2+、Ca2+One or more of (a).
According to another aspect of the present invention, there is provided a method for preparing the above-mentioned breviscapine injectable hydrogel, comprising dissolving breviscapine in an alkaline aqueous solution, adding metal ions, and performing ultrasound treatment to obtain the breviscapine injectable hydrogel.
Further, the time of ultrasound is 30s-120 s.
Further, the concentration of the metal ions is 0.02mol/L to 0.5 mol/L. Too low concentration of metal ions can result in the formation of hydrogel by coordination and self-assembly with breviscapine, and too high concentration can result in the non-uniform transparency of the gel. In the present invention, the concentration of the metal ion is preferably 0.02mol/L to 0.5mol/L, and the effect is most excellent.
According to another aspect of the present invention, an application of the above-mentioned breviscapine injectable hydrogel or the breviscapine injectable hydrogel obtained by the above-mentioned preparation method is provided, and the breviscapine injectable hydrogel is used for development of injection formulations of drugs for cerebral ischemia reperfusion, cerebral hemorrhage, cerebral trauma and myocardial infarction.
Compared with the prior art, the invention has the following beneficial effects:
the invention utilizes the clinical medicine breviscapine and the metal ion coordination self-assembly to form the injectable hydrogel, and the medicine molecules do not need chemical modification and other carriers, thereby improving the medicine-loading rate and the safety; the hydrogel can rapidly deliver the drug to a target position through an injection mode; the hydrogel can be self-delivered and self-sustained released, and has good biocompatibility and biodegradability. The microstructure of the injectable breviscapine hydrogel prepared by the invention is a three-dimensional network, so that breviscapine drug molecules can be slowly released, the sustained-release capacity is realized, the drugs can be prevented from being rapidly removed, and the utilization rate of the drugs is improved. The breviscapine injectable hydrogel does not need chemical modification and additional carriers, has high drug utilization rate, has shear thinning and self-repairing performance, can be directly injected for administration, and has good slow release property and biocompatibility; the preparation method is green, environment-friendly and simple.
Drawings
FIG. 1 is a photograph showing the appearance of an injectable hydrogel of seven groups of adonixin according to example 1 of the present invention.
Fig. 2 is a graph of the self-repairing performance of the breviscapine injectable hydrogel of embodiment 2 of the present invention, which undergoes shear thinning under a certain stress.
Fig. 3 is a Scanning Electron Microscope (SEM) image of the breviscapine injectable hydrogel in example 2 of the present invention.
Fig. 4 is a sustained release curve chart of the breviscapine injectable hydrogel in embodiment 3 of the present invention.
FIG. 5 is a comparison graph of cytotoxicity of breviscapine solution (Sol in the figure) and breviscapine injectable hydrogel (Gel in the figure) in example 4 of the present invention.
Fig. 6 is a blood safety diagram of the breviscapine injectable hydrogel in example 5 of the present invention.
Detailed Description
In order to facilitate an understanding of the present invention, the present invention will be described more fully and in detail with reference to the preferred embodiments, but the scope of the present invention is not limited to the specific embodiments described below.
Unless otherwise defined, all terms of art used hereinafter have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.
Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods.
Example 1:
the preparation method of the breviscapine injectable hydrogel comprises the following steps:
weighing 13.0mg of breviscapine, putting into a screw bottle, adding 1mL of PBS buffer solution (pH 12.4), and performing ultrasonic treatment for 60s to dissolve to obtain breviscapine solution, wherein the content of breviscapine is 1.3 wt%; then adding 0.1mol/L zinc acetate solution into the breviscapine solution to ensure that the molar ratio of breviscapine to zinc ions is 1: 0.4; performing ultrasonic treatment for 30-60 s to obtain orange breviscapine injectable hydrogel with pH of 7.0. The appearance of the injectable hydrogel of breviscapine was recorded with a digital camera, and its appearance photograph is shown in No. 3 bottle in FIG. 1.
The preparation method of the breviscapine injectable hydrogel of the bottles No. 1, No. 2 and No. 4-6 in the figure 1 is similar to that of the preparation method of the breviscapine injectable hydrogel of the seven groups of erigeron breviscapus, and the preparation methods are only different in the molar ratio of the breviscapine to the metal ions. The mole ratio of breviscapine to metal ions in the bottle No. 1-7 in figure 1 is respectively: 1: 0.2; 1: 0.33; 1: 0.4; 1: 0.42; 1: 0.5; 1: 0.6; 1: 0.8.
as can be seen from FIG. 1, with the different molar ratios of breviscapine to metal ions in bottles No. 1-7, the breviscapine changed from solution state (bottle No. 1) to gel state, and the hydrogel formed by breviscapine was orange red, uniform and transparent.
Example 2:
the preparation method of the breviscapine injectable hydrogel comprises the following steps:
weighing 10.0mg of breviscapine, putting into a screw bottle, adding 1mL of PBS buffer solution (pH 12.8), and performing ultrasonic treatment for 60s to dissolve to obtain breviscapine solution, wherein the content of breviscapine is 1.0 wt%; then adding 0.05mol/L zinc acetate solution into the breviscapine solution to ensure that the molar ratio of breviscapine to zinc ions is 1: 0.6; performing ultrasonic treatment for 30-60 s to obtain orange breviscapine injectable hydrogel with pH of 7.0.
And testing the shear thinning and self-repairing capability of the breviscapine hydrogel by using a rheometer. We reacted to the state of the hydrogel by detecting changes in storage modulus (G ') and loss modulus (G'). When G '> G', the sample is in a gel state; when G '< G', the sample is in a solution state.
The specific testing steps are as follows: placing the prepared hydrogel on a rheometer, setting experiment parameters, and dividing the experiment into three stages: in the first stage, under low stress, the stress is set to be 0.1 percent, and the time is 180 s; in the second stage, under high stress, the stress is set to be 30 percent, and the time is kept for 60 s; the third stage was returned to a low stress of 0.1% stress for a period of 180 seconds from a high stress, and the change in each of stages G' and G "was observed.
As shown in fig. 2, in the first stage, at a low stress of 0.1%, the storage modulus (G') is always greater than the loss modulus (G ″), indicating that the sample is in a gel state; in the second stage, when the stress is increased to 30%, the storage modulus (G ') is always smaller than the loss modulus (G'), which indicates that the sample is in a solution state: in the third stage, the storage modulus (G ') is greater than the loss modulus (G') when returning from high stress to low stress, indicating that the sample changes from the solution state back to the gel state when the stress is reduced. The tests show that the breviscapine hydrogel has good shear thinning and self-repairing capabilities.
Observing the microstructure of the breviscapine injectable hydrogel by using a Scanning Electron Microscope (SEM). 10 μ L of hydrogel was placed on a clean silicon wafer, lyophilized for 24h, and then tested. And carrying out gold spraying treatment before scanning due to poor conductivity of the sample. Fig. 3 is a scanning electron microscope image of the breviscapine injectable hydrogel obtained in the present example. As shown in FIG. 3, the micro-morphology of the breviscapine hydrogel is a three-dimensional network structure.
Example 3:
the preparation method of the breviscapine injectable hydrogel comprises the following steps:
weighing 10.0mg of breviscapine in two screw bottles, respectively adding 1.0mL of PBS solution (pH 12.0), and performing ultrasonic treatment for 1min to obtain breviscapine solution; adding 120 mu L of zinc acetate solution into the breviscapine solution to ensure that the molar ratio of breviscapine to zinc ions is 1: 0.8; and (5) carrying out ultrasonic treatment to obtain the breviscapine hydrogel.
And then, measuring the drug slow-release capacity of the breviscapine hydrogel. The detection method comprises the following steps: putting 1.0mL of breviscapine hydrogel into a dialysis bag, putting the dialysis bag into a beaker filled with 200mL of LPBS (0.01mol/L, pH 7.4), and putting the beaker into a constant-temperature incubator (the temperature is 37 ℃ and the rotating speed is 80 r/min); at different time points, 1mL of PBS was taken out of the beaker and 1mL of fresh PBS was added; and detecting the absorbance of the sample by using ultraviolet absorption spectrum, calculating the cumulative release amount of the drug, and drawing a drug cumulative release curve.
Fig. 4 shows the drug sustained release curve of the breviscapine injectable hydrogel prepared in this example. As can be seen from FIG. 4, the breviscapine injectable hydrogel can be slowly released for more than 5 days.
Example 4:
adding 10% fetal calf serum into mouse hippocampal neuron cell strain HT22 in DMEM culture medium, and adding double antibody; carrying out pancreatin digestion and passage until about 70% of cells are fused, then carrying out pancreatin digestion, preparing cell suspension, and then carrying out cell counting under a microscope; then seeded in 96-well plates, 2.5 x 10^3 cells per well. After the cells are attached to the wall, the breviscapine solution and the breviscapine hydrogel are treated, and the concentration gradient is 0.1 mu g/mL, 1 mu g/mL and 10 mu g/mL. Change in cell proliferation 24 hours after photodifferential administration by the CCK8 method. After 24 hours, the medium was aspirated, 10. mu.L of CCK8 was added to 100. mu.L of the medium per well, incubated at 37 ℃ for 1.5 hours, and the OD was measured at 450nm using a microplate reader. And calculating the proliferation effect of the breviscapine and the breviscapine hydrogel on the HT22 cells.
The cell survival rate (%) calculation method was:
survival (%) (administration well OD-blank well OD)/(control well OD-blank well OD) × 100%
FIG. 5 shows the result of CCK8, and compared with the breviscapine solution, the breviscapine hydrogel of the present invention can significantly promote the proliferation of HT 22.
Example 5:
preparing a red blood cell suspension:
blood of a C57BL/6 mouse is collected in a heparin sodium anticoagulation tube by an eyeball blood taking method, 1mL of whole blood is removed, 2.5 mL of sterilized PBS is added to be centrifuged at 2000r/min for 5min for cleaning, the supernatant is discarded, the operation is repeated three times, and red blood cells are collected. 100 μ L of red blood cells was added to 4.9mL of sterile PBS to obtain a 2% suspension of red blood cells.
Testing hemolytic performance:
breviscapine hydrogel group: 20 mu L of breviscapine injectable hydrogel of the present invention is added into a 1.5mL centrifuge tube, then 1mL of red blood cell suspension is added, and the mixture is kept standing for 1 hour at 37 ℃. Breviscapine solution group: mu.L of the solution was added to a 1.5mL centrifuge tube, followed by 1mL of the red blood cell suspension, and the mixture was allowed to stand at 37 ℃ for 1 hour. Positive control group: mu.L of TritonX-100 (1% v/v) was added to a 1.5mL centrifuge tube, followed by 1mL of red blood cell suspension, and incubation was performed at 37 ℃ for 1 hour. Negative control group: mu.L PBS was added to a 1.5mL centrifuge tube, followed by 1mL red blood cell suspension, and allowed to stand at 37 ℃ for 1 hour.
After 1 hour, the tubes were centrifuged at 2000r/min for 5min and the supernatant was collected and the absorbance was measured at 540 nm. The absorbance of the supernatant of the TritonX-100 group at 540nm is taken as the hemolysis rate of 100%, the absorbance of the supernatant of the PBS group at 540nm is taken as the hemolysis rate of 0%, and the hemolysis rates of the breviscapine solution group and the breviscapine hydrogel group of the invention are calculated.
As shown in FIG. 6, the supernatant of red blood cells treated by TritonX-100 is bright red and has strong hemolytic property, while the supernatant of red blood cells treated by breviscapine solution and breviscapine hydrogel of the present invention is clear and has an absorbance at 540nm equivalent to that of PBS blank group. The breviscapine injectable hydrogel hardly causes hemolysis under the concentration condition, and shows good blood compatibility.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The injectable breviscapine hydrogel is characterized in that the injectable breviscapine hydrogel is formed by coordination and self-assembly of breviscapine and metal ions in an alkaline aqueous solution.
2. The breviscapine injectable hydrogel according to claim 1, wherein the content of breviscapine in the breviscapine injectable hydrogel is 0.8 wt% to 4.0 wt%.
3. The breviscapine injectable hydrogel of claim 1, wherein the pH of the basic aqueous solution is 10 to 12.8, and the pH of the hydrogel is 7.0 to 7.4.
4. The breviscapine injectable hydrogel according to claim 1, wherein the basic aqueous solution is a PBS buffer solution, a sodium hydroxide solution or a potassium hydroxide solution.
5. The breviscapine injectable hydrogel according to claim 1, wherein the molar ratio of breviscapine to the metal ions is 1: (0.33-1.2).
6. The breviscapine injectable hydrogel of claim 1, wherein the metal ion is Zn2+、Ca2+One or more of (a).
7. A method for preparing the breviscapine injectable hydrogel according to any one of claims 1 to 6, wherein the breviscapine injectable hydrogel is prepared by dissolving breviscapine in an alkaline aqueous solution, adding a metal ion solution, and performing ultrasonic treatment.
8. The method of claim 7, wherein the sonication time is 30-120 s.
9. The method according to claim 7, wherein the concentration of the metal ion solution is 0.02mol/L to 0.5 mol/L.
10. The use of the breviscapine injectable hydrogel according to any one of claims 1 to 6 or the breviscapine injectable hydrogel obtained by the preparation method according to any one of claims 7 to 9, wherein the breviscapine injectable hydrogel is used for the development of injection formulations of cerebral ischemia reperfusion, cerebral hemorrhage, cerebral trauma and myocardial infarction drugs.
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Citations (5)
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| CN105061538A (en) * | 2015-06-04 | 2015-11-18 | 姚瑞星 | Scutellarin metal coordination compound preparation |
| CN106667986A (en) * | 2017-01-24 | 2017-05-17 | 中南大学湘雅医院 | Rhein/chitosan hydrogel as well as preparation method and application thereof |
| US20170273886A1 (en) * | 2014-09-30 | 2017-09-28 | Allergan Industrie, Sas | Stable hydrogel compositions including additives |
| CN108484709A (en) * | 2018-03-05 | 2018-09-04 | 承德绿源生物科技有限公司 | Lamp-dish flower acetic magnesium compound, preparation method and application |
| CN110585120A (en) * | 2019-10-08 | 2019-12-20 | 中南大学 | Injectable diacerein hydrogel and preparation method thereof |
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- 2021-08-24 CN CN202110976650.XA patent/CN113797157A/en active Pending
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| US20170273886A1 (en) * | 2014-09-30 | 2017-09-28 | Allergan Industrie, Sas | Stable hydrogel compositions including additives |
| CN105061538A (en) * | 2015-06-04 | 2015-11-18 | 姚瑞星 | Scutellarin metal coordination compound preparation |
| CN106667986A (en) * | 2017-01-24 | 2017-05-17 | 中南大学湘雅医院 | Rhein/chitosan hydrogel as well as preparation method and application thereof |
| CN108484709A (en) * | 2018-03-05 | 2018-09-04 | 承德绿源生物科技有限公司 | Lamp-dish flower acetic magnesium compound, preparation method and application |
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